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in the circulation and in the renal tissue of diabetic and nondiabetic nephropathies. The
increased RAAS activity plays an important role in the hemodynamic and
nonhemodynamic pathogenetic mechanisms involved in kidney disease. Previous studies
have demonstrated that albuminuria is not only a marker of glomerular lesions, but also a
progression promoter, and finally a powerful predictor of the long-term beneficial effect of
blood pressure-lowering therapy. Randomized crossover and parallel blind studies in
patients with diabetic nephropathy have demonstrated that angiotensin II receptor blockers
(ARB) induce favorable changes in systemic blood pressure, renal hemodynamics, and
proteinuria similar to those induced by angiotensin-converting enzyme (ACE) inhibition.
Studies have revealed the optimal renoprotective dose for some ARBs; however, additional
dose titration studies are urgently needed to obtain the maximum benefit of this valuable
new class of compounds. The combination of ARB and ACE inhibition is well tolerated
and even more effective than monotherapy in reducing systemic blood pressure and
albuminuria in diabetic nephropathy. In addition, dual RAAS blockade is safe and well
tolerated. Impaired autoregulation of glomerular filtration rate (GFR); demonstrated with
some blood pressure-lowering agents implies disturbances in the downstream transmission
of the systemic blood pressure into the glomerulus, leading to capillary hypertension or
hypotension depending of the level of blood pressure. ARB does not interfere with GFR
autoregulation in hypertensive diabetic patients. In contrast to previous observational
studies with ACE inhibition, long-term treatment with ARB has similar beneficial
renoprotective effect on progression of diabetic kidney disease in hypertensive diabetic
patients with ACE II and DD genotypes. ARB can prevent/delay development of diabetic
nephropathy independently of its beneficial blood pressure-lowering effect in patients with
type 2 diabetes and microalbuminuria. Recently, two landmark studies led to the following
conclusion: Losartan and Irbesartan conferred significant renal benefit in patients with
type 2 diabetes and nephropathy. This protection is independent of the reduction in blood
pressure it causes. The ARB is generally safe and well tolerated. A recent metaanalysis
indicates that ARBs reduce cardiovascular events mainly because of reduction in first
hospitalization for congestive heart failure in hypertensive type 2 diabetic patients with
albuminuria. The studies mentioned here suggest that ARB represents a beneficial
treatment of hypertension and proteinuria in incipient and overt diabetic nephropathy.
At first sight, it might seem paradoxical to treat diabetic nephropathy by inhibition of the
reninangiotensinaldosterone system (RAAS), because the blood renin levels in diabetic
subjects are low rather than high [5].
RAAS and its blockade in diabetic nephropathy
Recent human and experimental studies have revealed that there is an increased local
activity of the RAAS and an increased production of angiotensin II (Ang II) in the kidney
[5]. Ang II has known cardiovascular and renal-damaging effects: vasoconstriction,
increase in aldosterone secretion, growth, fibrosis, thrombosis, inflammation and
oxidation, which are mediated by the angiotensin AT1 receptor [6]. Consequently,
prevention of the effects of Ang II mediated by the AT1 receptor seems to have a beneficial
effect on the progression of diabetic nephropathy [7]. It was demonstrated earlier that
blockade of the RAAS by angiotensin-converting enzyme inhibitors (ACEIs) can have a
beneficial effect on the progression of diabetic nephropathy [8]. This specific
nephroprotective effect may be explained by the vasodilatating effects of ACEIs on the
glomerular efferent arterioles. Clinical trials have confirmed the beneficial effect of these
treatments: ACEIs decreased the proteinuria and attenuated the progression of the renal
disease in diabetic subjects [9]; however, according to other published data, ACEIs were
not superior to other antihypertensive agents in slowing down the progression of type 2
diabetic nephropathy [10].
Angiotensin receptor blockers (ARBs) represent a new class of antihypertensive drugs that
block the RAAS. They selectively block the AT1 receptor and in this way inhibit the
vasoconstrictive and tissue-damaging effects of Ang II in diabetes, including growth,
inflammation and thrombosis.
Trials with AT1 receptor blockers in type 2 diabetic nephropathy
Three trials recently have studied the ARBs in patients with diabetic nephropathy.
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan
(RENAAL) study investigated the effects of the ARB, losartan, in 1513 patients with type
2 diabetes and nephropathy [11]. In this study, which lasted for 3.4 years, one group
received losartan, while the other group received conventional antihypertensive agents
(placebo group). The target BP was <140/90 mmHg. The main question was whether the
treatment with losartan could influence the primary end-point (the composite of death,
ESRD and doubling of serum creatinine) and the secondary end-points (composite of
morbidity and mortality from cardiovascular causes, proteinuria and the rate of progression
of the renal disease).
Losartan reduced the relative risk of the primary composite end-point as compared with the
placebo group by 16% (P < 0.02), reduced the incidence of doubling of serum creatinine
by 25% (P < 0.006) and reduced ESRD by 28% (P < 0.02). The proteinuria was also
significantly decreased. Extrapolating from the observed data, this reduction corresponds
to an average delay of 2 years in the need for dialysis or transplantation as estimated by the
authors. There was no significant difference in relation to the risk of death, or
cardiovascular morbidity and mortality.
The Irbesartan Diabetic Nephropathy Trial (IDNT) investigated the effects of irbesartan
and amlodipine on the rate of progression of diabetic nephropathy in 1715 subjects with
type 2 diabetic nephropathy [12]. The duration of the study was a mean of 2.6 years. The
first group was treated with irbesartan, the second with amlodipine and the third with
conventional antihypertensive drugs (placebo group). It was planned to achieve a BP goal
of <135/85 mmHg. The primary and secondary end-points were very similar to those in the
RENAAL study.
Irbesartan demonstrated a relative risk (RR) reduction vs placebo by 20% of the composite
end-point (P < 0.02), by 33% of the doubling of serum creatinine (P < 0.003) and by 23%
of ESRD (P < 0.07). Irbesartan displayed an even more significant RR reduction vs
amlodipine, by 23% of the composite end-point (P < 0.006), and by 37% of the doubling of
serum creatinine (P < 0.001). In this comparison, the incidence of ESRD was on the
borderline of significance, vs both the placebo and amlodipine. The ARB treatment
significantly decreased the proteinuria. The RR of death, cardiovascular morbidity and
mortality was not significantly changed in either comparison.
Not only the design of the two studies with ARBs (RENAAL and IDNT), but also the
results were very similar. From these data, we realized that the more beneficial
nephroprotective effect of the ABRs starts to differ from that of conventional therapy only
after 1.5 years and that the difference becomes significant later. There are minor
differences between the results of the RENAAL and IDNT studies. Regarding the
incidence of ESRD, this was decreased in both studies, but the decrease was not significant
in the IDNT study. Considering that the duration of the IDNT study was shorter (2.6 years)
than the RENAAL study (3.4 years), we could assume that, if the IDNT study had lasted
longer, the decrease in ESRD would have been significant. The highly significant RR of
doubling of the serum creatinine supports this assumption. From the above-mentioned data,
we can conclude that to study the effect of a therapy on diabetic nephropathy, the trial
should be designed to last longer (probably not less than 3.54 years).
Both the RENAAL and the IDNT study have shown that losartan and irbesartan have
specific nephroprotective effects, independently of the BP reduction. These results indicate
that the ARBs have an important role in the management of patients with type 2 diabetic
nephropathy.
The third trial, IRbesartan MicroAlbuminuria in hypertensive patients with type 2 diabetes
(IRMA 2), was carried out in 520 subjects with type 2 diabetes, who were followed for 2
years [13]. The patients had persistent microalbuminuria and a normal renal function. One
group of patients received irbesartan, while the placebo group was treated with
conventional antihypertensive agents to achieve the target BP of <135/85 mmHg.
The primary end-point was the time of development of diabetic nephropathy. Irbesartan
revealed a 39% RR reduction vs placebo in the development of nephropathy (P < 0.001).
This study confirmed that the ARB, irbesartan, has a specific antiproteinuric effect. The
question still remains of how much this treatment can prevent the development of diabetic
nephropathy.
As previously discussed, both the ACEIs and ARBs have a specific nephroprotective effect.
Since Ang II may be produced through other pathways, involving enzymes other than ACE
(e.g. chymase), it would be worthwhile to investigate whether the combination of an ACEI
and an ARB with a theoretically more extensive blockade of the RAAS would have a more
efficient nephroprotective effect than the two agents alone.
The worldwide largest (n = 28 400) trial to date is the Ongoing Telmisartan Alone in
combination with Ramipril Global Endpoint Trial (ONTARGET). This trial recently started
in type 2 diabetic patients, to investigate the effects of combined ACEIARB therapy. The
patients will be treated randomly with telmisartan or ramipril separately and with a
combination of the two agents. In addition to the primary composite (of cardiovascular
death) and secondary end-points, the occurrence of nephropathy will be investigated.
Experience in the recent past indicated that the most successful strategy for the treatment
of diabetic nephropathy is the inhibition or blockade of the RAAS, using ACEIs or ARBs
[4,14].
Conclusion
Many studies suggest promising steps in the development of therapeutic approaches to
prevent or to decrease the rate of progression of type 2 diabetic nephropathy. The recently
published data from many trials suggest that the antihypertensive ARB agents have a
slowing effect on the progression of diabetic nephropathy and on the development of
proteinuria in type 2 diabetes. Accordingly, ARBs are useful to treat type 2 diabetic
nephropathy.
Effects
of
AT1 receptor
blockade
during
stress.
Peripheral
administration of the AT1 antagonist candesartan blocks brain AT1 receptors and
prevents the hormonal and sympathoadrenal response to isolation stress.
To determine whether or not Ang II and AT1 receptors played significant roles in
the regulation of the stress reaction, we studied the response of the organism to
stress a f t e r s u s t a i n e d b l o c k a d e o f p e r i p h e r a l a n d b r a i n A T 1
r e c e p t o r s . We f i r s t d e v e l o p e d a n a n i m a l m o d e l o f b r a i n AT1 receptor
blockade after peripheral administration of the receptor antagonist, a model necessary to
relate our findings i n a m e a n i n g f u l w a y t o c l i n i c a l c o n d i t i o n s i n
h u m a n populations. We found that peripheral administration of a selective, potent,
insurmountable
AT1
antagonist
such
as
candesartan[6971],
when
only
that
candesartan
readily
crosses
the
blood
brain
from
freely
regulating
exposure
to
novel
adrenal
aldosterone[54],
metabolites,
transcription
of
catecholamines
tyrosine
and
hydroxylase,
the
corticosterone
and
the
rate-limiting
( Fig. 6),
adrenal
enzyme
in
vasopressin
(F i g .
6)
during
isolation,
decreased
the
centrally
acting
insurmountable
AT1
antagonists
such
as
c a n d e s a r t a n c o u l d h a v e a p l a c e i n t h e t h e r a p y o f stress-related disorders.
Effect of pretreatment with candesartan on an acute stress induced disorder
To establish whether or not AT1 receptor blockade could be of therapeutic benefit, we
initiated a study of the effects o f c a n d e s a r t a n o n t h e d e v e l o p m e n t
of
stress-induced
candesartan o n
disorders. We first
studied
the
effect
of
in
leukocyte
muscular
activation
contractility,
and
mast
increased
cell
degranulation,
free
radical generation
factors,
and
Ang
II,
through
AT 1
number
of
ulcerations
produced
by
cold-restraint
in
the
blood
flow
after
administration
of
of
A T 1 receptor
that
stress
proinflammatory
adhesion
markedly
cytokine
molecule
increased
tumor
the
necrosis
intercellular
expression
factor a
of
(TNF-a) ,
the
the
adhesionm o l e c u l e - 1
through
stress
may
contribute
to
c a n d e s a r t a n , b e c a u s e c o r t i c o i d s have
the
therapeutic
effect
of